This invention relates in general to a process for making fused medicinal implants, preferably in the form of cylindrical pellets for the subcutaneous implantation and delivery of drugs and in particular to a process for making a fused implant for fertility control and certain endocrinologically mediated disorders.
It has become widely acknowledged that standard oral and parenteral (intravenous or intramuscular) forms of drug delivery represent relatively inefficient means of administering therapeutic pharmaceuticals, due to considerable drawbacks associated with conventional drug-delivery methods. These drawbacks arise from the way in which standard dosage forms of pharmacologically active compounds are absorbed into the body, circulated through the blood stream, cleared and excreted. Conventional routes of administration generally require the administration of far more of a drug than is therapeutically warranted so that there will be adequate blood levels of drug between doses ("spiking"). Moreover, there are many therapeutically vital substances which present a narrow ratio of efficacy to toxicity that do not, therefore, lend themselves to traditional routes of administration. Additionally, drugs that require daily compliance with a multiple-dose regimen on the part of the patient pose a major problem in the management of the chronically ill, elderly, those with emotional disorders, and people whose lifestyles do not comfortably accommodate regular routine. The lists of conditions requiring such regimens is extensive and includes: diabetes; psychiatric diseases; cancer; and coronary artery disease, to name only a few.
In recent years, various types of novel sustained release drug-delivery systems have begun to receive widespread attention. Such drug-delivery systems include certain implantable devices which slowly dissolve or somehow release drugs while under the patient's skin. Implants are particularly effective and economical forms of treatment because a single administration of such a product can deliver, over a long period of time (a year or more), adequate therapeutic serum levels of a drug without reliance on patient compliance, frequent clinic visits and while avoiding over medication due to "spiking". Known implantable systems have drawbacks. Some are not long-acting enough; some have what are called poor kinetics, which cause them to release drug in less even and predictable amounts over time; some are too long in duration; some are irreversible (impossible to discontinue, once begun); and others require surgical removal when the system is depleted of drug.
Implantable systems for fertility control, as well as for other clinical applications, have long been sought as an alternative to oral preparations of steroids. This approach is particularly attractive to developing nations, where national health-care networks are at a disadvantage in reaching a population which is demographically and educationally ill controlled. Moreover, significant potential health problems associated with the use of certain steroids have raised many questions as to the wisdom of prescribing steroids in the amounts required for effective oral delivery. A progestogen--only implant for fertility control, the Silastic implant--NORPLANT.RTM.--has been extremely well accepted in fertility control trials throughout the world despite the cumbersome nature of multiple, one-inch or longer rods that must be surgically implanted and removed when depleted. The subject of the current invention includes a process which yields a bioerodable fused pellet coupling active and nonactive ingredients and prepared for subdermal implantation, which reduces the disadvantages of the known long term implantable drug delivery systems.
It is known that bioabsorbable implants can be made by various methods and utilizing various materials. Several methods have been practiced with steroid drugs. For example, a bioabsorbable implant can be made by tightly compressing powdered steroid. An improved implant results from compressing a combination of a nonactive biocompatible binder and the steroid into a pellet which pellet releases steroid more slowly and more uniformly than the pure steroid pellets.
An important improvement over the compression process for making pellets which results in even longer and more constant dissolution rates, is a method of melting a drug together with a sufficient amount of a nonactive lipoid carrier resulting, when cooled, in a "fused" pellet. The superior kinetics and release rates are believed to be due to the final integral crystal lattice produced from the starting materials. It has been suggested that such a "fused" implant of a sex steroid uniformly dispersed with a suitable lipoid carrier may provide a convenient, safe and effective form of long-term fertility control in mammals. Specifically, a precise intimate mixture of the starting materials in their micronized crystalline form, as supplied by the manufacturer, is heated according to the published melting points of either the active ingredient or the carrier or to a eutectic point of the two where a phase change occurs and an isotropic liquid (perfectly clear melt) is achieved. At this point, the materials are allowed to cool or are quenched whereupon the melt hardens through recrystallization into the final, integral "fused" pellet. Such fused implants, however, have proven unsuitable for a variety of reasons, largely related to the manufacturing processes used which are not easily reproducible. The background of such fused implants is discussed in greater detail in U.S. Pat. No. 4,244,949 (Gupta).
The methods suggested by Gupta and others for making such a fused implant rely heavily upon manual skills, have a very low yield of effective final product when performed by anyone unpracticed in the procedure and do not lend themselves to automated mass production techniques. In particular, the best of the prior art methods known to applicant requires pre measuring and dispensing into very small vessels minute amounts of active ingredient and carrier. The material must be gradually heated within a vessel while gently applying a continuous pressure, with steel rods, at each end of the vessel until a clear liquid phase is determined by eye. Then the melted material is removed from the heat source and allowed to cool. This human-dependent process not only is inefficient, but is more a craft than a practicable method capable of being reproduced consistently. This is especially important as it relates to the Good Manufacturing Practices promulgated by the FDA as necessary for the commercial approval of any drug.
The requirement of delicate manipulations and skilled judgment on the part of an individual introduces a potential for error with the making of each pellet. The duration of which the material is exposed to temperature is not adequately controlled according to prior art methods and the material may be overheated, causing de-ethynylation of the active ingredient. This effect has been misunderstood in previous art resulting in the presumption that oxidation--an atmospheric effect--was the cause of degradation of the final product. Therefore, this art sought to avoid open air or atmosphere melts and introduced manufacturing steps that actually created a greater likelihood of both degradation due to duration of heat exposure as well as the "capturing" of gases within the final product. Moreover, cumbersome procedural steps and apparatus were introduced to avoid open air melts.
The pressure applied to the melt also is not quantitatively controlled according to these prior art methods. Also, the integrity of the final crystal of the fused pellet may be adversely affected by transverse fractures and friability as the crystal forms when the melt is manually removed from the heat source. Pre-measuring and dispensing of the ingredients by hand into the vessels introduces the potential for error and contamination. Moreover, this practice necessitates an undesirable degree of human exposure to steroids in powder form, demanding the strictest controls according to the rules promulgated by the FDA. Also, certain of the prior art methods require purification of the starting materials by recrystallizing them using various solvents, nitrogen chambers and dessicators in order to assure that gases or moisture were eliminated from the crystals.
Applicant's invention overcomes these and other shortcomings. Applicant provides a process for forming a fused pellet that does not require the skilled manipulation and human judgment previously enumerated and that is capable of automation and suitable for large scale commercial production. Applicant also provides a process for forming a fused implant that does not result in de-ethynylation or other degradation products of the starting materials. Applicant's process for forming a fused pellet further does not require an oxygen free environment and does not "trap" air or gases, but rather allows the free evaporation of impurities which otherwise might be collected within the tortuous geometry of the individual crystals of the starting materials.
Another object of the invention is to provide a process for dispensing the intimate mixture in precise relative amounts in an automated fashion where the active ingredient comprises over 50% of the final drug product.